Generalized morphea following COVID‐19 vaccine: Case report and literature review

Abstract Physicians should be vigilant for COVID‐19 vaccine side effects and investigate any associated cutaneous manifestations. This will ultimately facilitate better understanding and recognition of various skin reactions related to the vaccine.


| INTRODUCTION
Adverse muco-cutaneous manifestations were increasingly observed following COVID-19 vaccinations, highlighting that such unfortunate cutaneous reactions are not only secondary to SARS-CoV-2 infection but rather can be related to COVID-19 vaccines. 1,2 Particularly, Type 1 hypersensitivity reactions such as angioedema, anaphylaxis, and urticaria. Also, Type 4 hypersensitivity reactions such as erythema multiforme-like rashes, morbilliform, and inflammatory markers at the injection site. 1,2 Furthermore, there are other cutaneous manifestations that were reported in the literature, including cutaneous vasculitis, pityriasis rosea-like reactions, functional angiopathies, lichenoid drug eruptions, and herpes zoster reactivations. [2][3][4][5] The development of morphea secondary to vaccination is rare and the reported cases appear to be in predisposed patients, the majority of whom were children. Although the main mechanism behind it is still unknown, it was hypothesized to be due to antigenic cross-reactivity between human tissues and vaccine spike proteins. This could subsequently result in immune-mediated diseases like generalized morphea, where memory cells and antibodies are produced. 6,7 Additionally, polyarthritis, myocarditispericarditis, autoimmune disease flares, and delayed cutaneous reactions are further examples of immune-related diseases and autoimmune activities that might result following the aforementioned interaction. 6 Physicians should be vigilant for COVID-19 vaccine side effects and investigate any associated cutaneous manifestations. This will ultimately facilitate and establish a better understanding and recognition of various skin reactions related to the vaccine. Currently there are few reported cases in the literature of morphea secondary to COVID-19 infection. 1,3 On the other hand, there T A B L E 1 All the reported cases in the literature of patients developing morphea following COVID-19 vaccine including this case report. The table compares all the cases based on several factors such as age, gender, COVID-19 vaccine type, interval between vaccination and symptoms, and other variables.  (Table 1). Herein, we present one of the rare cases of new-onset generalized morphea following COVID-19 vaccine. In addition, we shed light on similar reported cases.

| CASE REPORT
Our patient is a 63-year-old Saudi female, known case of hypertension and diabetes mellitus with uncontrolled blood sugar levels, on insulin and metformin. She presented to our clinic with erythematous and hyperpigmented sclerotic plaques over trunk and extremities. Interestingly, the patient noticed the lesions starting to appear 2 weeks after receiving her second dose of Pfizer-BioNTech COVID-19 vaccine 1 year ago. It first started as a solitary lesion over her right shoulder. Then, one to two new lesions were appearing every month. She denied any history of myalgia, arthralgia, or malaise. She had no personal or family history of autoimmune or dermatologic diseases. On physical examination, multiple scattered hyperpigmented atrophic hard plaques were seen over her left upper chest, axillae, abdomen, and back (Figures 1 and 2). A total of 13 lesions varying in size from 3 to 17.5 cm in diameter were observed. The largest one was located on the back as a centered linear hyperpigmented atrophic plaque with erythematous verrucous surface measuring (17.5 × 8 cm) (Figure 1a). Therefore, the following were considered as a possible diagnosis: necrobiosis lipoidica and morphea. Laboratory tests were requested and all of which were within the normal range such as CBC, LFT, RFT, electrolytes, and CRP except for an increase in her ESR:52. Lastly, her autoimmune profile (ANA, anti-DNA, anti-SSA, anti-SSB, anti-SM, anti-Jo1, anti-SCL70, anti-RNP, anti-centromere) was unremarkable. Subsequently, a 4-mm punch biopsy was done, which revealed thickened collagen bundles in the dermis with focal interstitial lymphocytes (Figure 3). The patient was prescribed methotrexate 15 mg weekly and her response to the treatment will be followed up and assessed. The timeline highlighting our patient's presentation is summarized in Figure 4.

| DISCUSSION
Vaccinations enhanced global health and eradicated fatal infectious diseases such as smallpox. There are concerns about vaccine-induced adverse events; however, its reported frequency in the most common vaccines ranges between 4.8 and 83.0 per 100,000 doses. 11,12 Vaccination may lead to the appearance of some dermatoses. Antoñanzas et al. have summarized distinct examples such as granuloma annulare development within a close temporal period following antitetanic vaccine administration. 7 Additionally, patients developed bullous pemphigoid, mast cell tumors, and lichen planus after receiving hepatitis B vaccination. In those patients, the skin manifestations appeared only a few weeks after they received their vaccines. Lesions also developed exactly at the vaccine injection site, which possibly suggests a causal relationship. 7 A total of nine patient presentations of morphea post-COVID-19 vaccination were reported in the literature. [6][7][8][9][10] Four of which were following Pfizer-BioNTech such as our case, three were post AstraZeneca vaccine, and one was post-Moderna vaccine. [6][7][8][9][10] Interestingly, all of the reported patients were female except one. The time interval before onset of lesions ranged between 2 and 15 days post-vaccine, and half of the patients reported onset after the first dose while the other half after the second dose of the vaccine. Table 1 summarizes all the reported cases including our case report, comparing all reported variables. COVID-19 vaccines can rarely cause immune dysregulation, which could consequently worsen an underlying condition or result in a new-onset of a skin manifestation. 10 F I G U R E 4 Represent the timeline of events in our case. Starting with the patient's history of developing solitary lesion shortly after receiving the second dose of Pfizer Covid-19 vaccine, and ending with the diagnosis of generalized morphea and its management.
Our patient developed generalized morphea 2 weeks after receiving her second dose of Pfizer-BioNTech COVID-19 vaccine. Using the WHO-UMC system for standardized causality assessment our patient's reaction falls under likely. 13 Moreover, morphea is also known as localized scleroderma, and is classified as an idiopathic, inflammatory, and sclerosing condition of the skin and subcutaneous tissue. It has been suggested that immune dysregulation plays a pivotal role in its pathogenesis along with genetic and environmental factors. 6 Usually the clinical presentation of morphea lesions are atrophic or indurated brownish plaques that develop at the injection site and can become generalized and might even lead to functional impairment. 6 Gambichler et al. concluded that due to the molecular mimicry between SARS-CoV-2 vaccine and human proteins, activation of autoreactive lymphocytes and recruitment of chemokines and cytokines leads to more widespread phenotype of autoimmune diseases. 2

| CONCLUSION
The pathogenesis of morphea is multifactorial. Immune dysregulation, genetic predisposition and environmental factors all play a role in disease activity. Dermatologic conditions related to COVID-19 vaccines could range from mild to severe forms. Thus, it needs to be carefully monitored and should not be treated lightly. Further studies are needed to investigate and highlight the mechanism by which COVID-19 vaccine results in morphea in certain people.